tbuckley/cabot-search huggingface dataset:
Intrinsic generation time of the SARS-CoV-2 Omicron variant: An observational study of household transmission
Authors: Mattia Manica, Alfredo De Bellis, Giorgio Guzzetta, Pamela Mancuso, Massimo Vicentini, Francesco Venturelli, Alessandro Zerbini, Eufemia Bisaccia, Maria Litvinova, Francesco Menegale, Carla Molina Grané, Piero Poletti, Valentina Marziano, Agnese Zardini, Valeria d'Andrea, Filippo Trentini, Antonino Bella, Flavia Riccardo, Patrizio Pezzotti, Marco Ajelli, Paolo Giorgi Rossi, Stefano Merler
Journal: The Lancet Regional Health - Europe (2022)

Starting from the final months of 2021, the SARS-CoV-2 Omicron variant expanded globally, swiftly replacing Delta, the variant that was dominant at the time. Many uncertainties remain about the epidemiology of Omicron; here, we aim to estimate its generation time.
Wound microenvironment self-adaptive hydrogel with efficient angiogenesis for promoting diabetic wound healing
Authors: Zijian Shao, Tianyu Yin, Jinbo Jiang, Yang He, Tao Xiang, Shaobing Zhou
Journal: Bioactive Materials (2022)

Neovascularization is critical to improve the diabetic microenvironment, deliver abundant nutrients to the wound and promote wound closure. However, the excess of oxidative stress impedes the healing process. Herein, a self-adaptive multifunctional hydrogel with self-healing property and injectability is fabricated through a boronic ester-based reaction between the phenylboronic acid groups of the 3-carboxyl-4-fluorophenylboronic acid -grafted quaternized chitosan and the hydroxyl groups of the polyvinyl alcohol, in which pro-angiogenic drug of desferrioxamine (DFO) is loaded in the form of gelatin microspheres (DFO@G). The boronic ester bonds of the hydrogel can self-adaptively react with hyperglycemic and hydrogen peroxide to alleviate oxidative stress and release DFO@G in the early phase of wound healing. A sustained release of DFO is then realized by responding to overexpressed matrix metalloproteinases. In a full-thickness diabetic wound model, the DFO@G loaded hydrogel accelerates angiogenesis by upregulating expression of hypoxia-inducible factor-1 and angiogenic growth factors, resulting in collagen deposition and rapid wound closure. This multifunctional hydrogel can not only self-adaptively change the microenvironment to a pro-healing state by decreasing oxidative stress, but also respond to matrix metalloproteinases to release DFO. The self-adaptive multifunctional hydrogel has a potential for treating diabetic wounds.
Loss of tau expression attenuates neurodegeneration associated with α-synucleinopathy
Authors: Scott C. Vermilyea, Anne Christensen, Joyce Meints, Balvindar Singh, Héctor Martell-Martínez, Md. Razaul Karim, Michael K. Lee
Journal: Translational Neurodegeneration (2022)

Abstract Background Neuronal dysfunction and degeneration linked to α-synuclein (αS) pathology is thought to be responsible for the progressive nature of Parkinson’s disease and related dementia with Lewy bodies. Studies have indicated bidirectional pathological relationships between αS pathology and tau abnormalities. We recently showed that A53T mutant human αS (HuαS) can cause post-synaptic and cognitive deficits that require microtubule-associated protein tau expression. However, the role of tau in the development of αS pathology and subsequent neuronal dysfunction has been controversial. Herein, we set out to determine the role of tau in the onset and progression of αS pathology (α-synucleinopathy) using a transgenic mouse model of α-synucleinopathy lacking mouse tau expression. Methods Transgenic mice expressing A53T mutant HuαS (TgA53T) were crossed with mTau −/− mice to generate TgA53T/mTau −/− . To achieve more uniform induction of α-synucleinopathy in mice, we used intramuscular injections of αS preformed fibrils (PFF) in non-transgenic (nTg), TgA53T, TgA53T/mTau −/− , and mTau −/− mice. Motor behavior was analyzed at 70 days post inoculation (dpi) of PFF and tissues for biochemical and neuropathological analysis were collected at 40 dpi, 70 dpi, and end stage. Results Loss of tau expression significantly delayed the onset of motor deficits in the TgA53T model and the progression of α-synucleinopathy disease, as evidenced by a significant reduction in histopathological and behavioral markers of neurodegeneration and disease, and a significant improvement in survival. In vitro application of PFF to primary mouse hippocampal neurons demonstrated no changes in PFF uptake and processing or pS129 αS aggregation as a function of tau expression. However, PFF-induced neurotoxicity, including morphological deficits in nTg neurons, was prevented with tau removal. Conclusions Collectively, our data suggest that tau is likely acting downstream of αS pathology to affect neuronal homeostasis and survival. This work further supports the investigation of tau in α-synucleinopathies to identify novel disease-modifying therapeutic strategies.
Autoimmune gastritis: long-term natural history in naïve<i>Helicobacter pylori</i>-negative patients
Authors: Massimo Rugge, Ludovica Bricca, Stefano Guzzinati, Diana Sacchi, Marco Pizzi, Edoardo Savarino, Fabio Farinati, Manuel Zorzi, Matteo Fassan, Angelo Paolo Dei Tos, Peter Malfertheiner, Robert M Genta, David Y Graham
Journal: Gut (2022)

Autoimmune gastritis (AIG) is an immunomediated disease targeting parietal cells, eventually resulting in oxyntic-restricted atrophy. This long-term follow-up study aimed at elucidating the natural history, histological phenotype(s), and associated cancer risk of patients with AIG consistently tested
Pentraxin 3 Inhibits Complement-driven Macrophage Activation to Restrain Granuloma Formation in Sarcoidosis
Authors: Relber A. Gonçales, Helder Novais Bastos, Cláudio Duarte-Oliveira, Daniela Antunes, Oksana Sokhatska, Maria Jacob, Rui Rolo, Cláudia F. Campos, Sergio D. Sasaki, Alessia Donato, Sarah N. Mapelli, Sandra Costa, Conceição Souto Moura, Luís Delgado, António Morais, Egídio Torrado, Frank L. van de Veerdonk, Thomas Weichhart, John D. Lambris, Ricardo Silvestre, Cecilia Garlanda, Alberto Mantovani, Cristina Cunha, Agostinho Carvalho
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Sarcoidosis is a multisystemic inflammatory disease characterized by the formation of granulomas in response to persistent stimuli. The long pentraxin PTX3 (pentraxin 3) has emerged as a component of humoral innate immunity with essential functions in the resolution of inflammation, but its role during granuloma formation is unknown. Objectives: To evaluate PTX3 as a modulator of pathogenic signals involved in granuloma formation and inflammation in sarcoidosis. Methods: Peripheral blood mononuclear cells obtained from patients with sarcoidosis harboring loss-of-function genetic variants and gene-deleted mice were used to assess the role of PTX3 in experimental models of granuloma formation in vitro and in vivo. The identified mechanisms of granulomatous inflammation were further evaluated in tissue and BAL samples and correlated with the disease course. Measurements and Main Results: We have identified a molecular link between PTX3 deficiency and the pathogenic amplification of complement activation to promote granuloma formation. Mechanistically, PTX3 deficiency licensed the complement component C5a-mediated activation of the metabolic checkpoint kinase mTORC1 (mammalian target of rapamycin complex 1) and the reprogramming of macrophages toward increased glycolysis to foster their proliferation and aggregation. This process sustained the further recruitment of granuloma-promoting immune cells and the associated proinflammatory microenvironment and influenced the clinical course of the disease. Conclusions: Our results identify PTX3 as a pivotal molecule that regulates complement-mediated signaling cues in macrophages to restrain granulomatous inflammation and highlight the therapeutic potential of this signaling axis in targeting granuloma formation in sarcoidosis.
Mucins MUC5AC and MUC5B Are Variably Packaged in the Same and in Separate Secretory Granules
Authors: Oanh N. Hoang, Anna Ermund, Ana M. Jaramillo, Dalia Fakih, Cory B. French, Jose R. Flores, Harry Karmouty-Quintana, Jesper M. Magnusson, Giorgio Fois, Michael Fauler, Manfred Frick, Peter Braubach, Joshua B. Hales, Richard C. Kurten, Reynold Panettieri, Leoncio Vergara, Camille Ehre, Roberto Adachi, Michael J. Tuvim, Gunnar C. Hansson, Burton F. Dickey
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

MUC5AC (mucin 5AC, oligomeric gel-forming) and MUC5B (mucin 5B, oligomeric gel-forming) are the predominant secreted polymeric mucins in mammalian airways. They contribute differently to the pathogenesis of various muco-obstructive and interstitial lung diseases, and their genes are separately regulated, but whether they are packaged together or in separate secretory granules is not known.
The IDentif.AI-x pandemic readiness platform: Rapid prioritization of optimized COVID-19 combination therapy regimens
Authors: Agata Blasiak, Anh T. L. Truong, Alexandria Remus, Lissa Hooi, Shirley Gek Kheng Seah, Peter Wang, De Hoe Chye, Angeline Pei Chiew Lim, Kim Tien Ng, Swee Teng Teo, Yee-Joo Tan, David Michael Allen, Louis Yi Ann Chai, Wee Joo Chng, Raymond T. P. Lin, David C. B. Lye, John Eu-Li Wong, Gek-Yen Gladys Tan, Conrad En Zuo Chan, Edward Kai-Hua Chow, Dean Ho
Journal: npj Digital Medicine (2022)

IDentif.AI-x, a clinically actionable artificial intelligence platform, was used to rapidly pinpoint and prioritize optimal combination therapies against COVID-19 by pairing a prospective, experimental validation of multi-drug efficacy on a SARS-CoV-2 live virus and Vero E6 assay with a quadratic optimization workflow. A starting pool of 12 candidate drugs developed in collaboration with a community of infectious disease clinicians was first narrowed down to a six-drug pool and then interrogated in 50 combination regimens at three dosing levels per drug, representing 729 possible combinations. IDentif.AI-x revealed EIDD-1931 to be a strong candidate upon which multiple drug combinations can be derived, and pinpointed a number of clinically actionable drug interactions, which were further reconfirmed in SARS-CoV-2 variants B.1.351 (Beta) and B.1.617.2 (Delta). IDentif.AI-x prioritized promising drug combinations for clinical translation and can be immediately adjusted and re-executed with a new pool of promising therapies in an actionable path towards rapidly optimizing combination therapy following pandemic emergence.
A systematic review of engagement reporting in remote measurement studies for health symptom tracking
Authors: Katie M. White, Charlotte Williamson, Nicol Bergou, Carolin Oetzmann, Valeria de Angel, Faith Matcham, Claire Henderson, Matthew Hotopf
Journal: npj Digital Medicine (2022)

Remote Measurement Technologies (RMTs) could revolutionise management of chronic health conditions by providing real-time symptom tracking. However, the promise of RMTs relies on user engagement, which at present is variably reported in the field. This review aimed to synthesise the RMT literature to identify how and to what extent engagement is defined, measured, and reported, and to present recommendations for the standardisation of future work. Seven databases (Embase, MEDLINE and PsycINFO (via Ovid), PubMed, IEEE Xplore, Web of Science, and Cochrane Central Register of Controlled Trials) were searched in July 2020 for papers using RMT apps for symptom monitoring in adults with a health condition, prompting users to track at least three times during the study period. Data were synthesised using critical interpretive synthesis. A total of 76 papers met the inclusion criteria. Sixty five percent of papers did not include a definition of engagement. Thirty five percent included both a definition and measurement of engagement. Four synthetic constructs were developed for measuring engagement: (i) engagement with the research protocol, (ii) objective RMT engagement, (iii) subjective RMT engagement, and (iv) interactions between objective and subjective RMT engagement. The field is currently impeded by incoherent measures and a lack of consideration for engagement definitions. A process for implementing the reporting of engagement in study design is presented, alongside a framework for definition and measurement options available. Future work should consider engagement with RMTs as distinct from the wider eHealth literature, and measure objective versus subjective RMT engagement.Registration: This review has been registered on PROSPERO [CRD42020192652].
Toward a Better Understanding of the Mechanisms and Pathophysiology of Anhedonia: Are We Ready for Translation?
Authors: Diego A. Pizzagalli
Journal: American Journal of Psychiatry (2022)

Anhedonia—the loss of pleasure or lack of reactivity to pleasurable stimuli—remains a formidable treatment challenge across neuropsychiatric disorders. In major depressive disorder, anhedonia has been linked to poor disease course, worse response to psychological, pharmacological, and neurostimulation treatments, and increased suicide risk. Moreover, although some neural abnormalities linked to anhedonia normalize after successful treatment, several persist—for example, blunted activation of the ventral striatum to reward-related cues and reduced functional connectivity involving the ventral striatum. Critically, some of these abnormalities have also been identified in unaffected, never-depressed children of parents with major depressive disorder and have been found to prospectively predict the first onset of major depression. Thus, neural abnormalities linked to anhedonia may be promising targets for prevention. Despite increased appreciation of the clinical importance of anhedonia and its underlying neural mechanisms, important gaps remain. In this overview, the author first summarizes the extant knowledge about the pathophysiology of anhedonia, which may provide a road map toward novel treatment and prevention strategies, and then highlights several priorities to facilitate clinically meaningful breakthroughs. These include a need for 1) appropriately controlled clinical trials, especially those embracing an experimental therapeutics approach to probe target engagement; 2) novel preclinical models relevant to anhedonia, with stronger translational value; and 3) clinical scales that incorporate neuroscientific advances in our understanding of anhedonia. The author concludes by highlighting important future directions, emphasizing the need for an integrated, collaborative, cross-species, and multilevel approach to tackling anhedonic phenotypes.
P-292 Endoscopic ultrasound guided-fine needle aspiration for the diagnosis of secondary pancreatic lesions. Experience of a reference center
Authors: P. Kevrekidou, E. Stergiou, R. Valeri, K. Soufleris, G. Lazaraki, N. Dimitriadis, D. Lazou, D. Tzilves
Journal: Annals of Oncology (2022)
A point-prevalence study on community and inpatient Clostridioides difficile infections (CDI): results from Combatting Bacterial Resistance in Europe CDI (COMBACTE-CDI), July to November 2018
Authors: Virginie F Viprey, Georgina L Davis, Anthony D Benson, Duncan Ewin, William Spittal, Jon J Vernon, Maja Rupnik, Alice Banz, Florence Allantaz, Philippe Cleuziat, Mark H Wilcox, Kerrie A Davies
Journal: Eurosurveillance (2022)

Background There is a paucity of data on community-based Clostridioides difficile infection (CDI) and how these compare with inpatient CDI. Aim To compare data on the populations with CDI in hospitals vs the community across 12 European countries. Methods For this point-prevalence study (July–November 2018), testing sites sent residual diagnostic material on sampling days to a coordinating laboratory for CDI testing and PCR ribotyping (n = 3,163). Information on whether CDI testing was requested at the original site was used to identify undiagnosed CDI. We used medical records to identify differences between healthcare settings in patient demographics and risk factors for detection of C. difficile with or without free toxin. Results The CDI positivity rate was 4.4% (country range: 0–16.2) in hospital samples, and 1.3% (country range: 0–2.2%) in community samples. The highest prevalence of toxinotype IIIb (027, 181 and 176) was seen in eastern European countries (56%; 43/77), the region with the lowest testing rate (58%; 164/281). Different predisposing risk factors were observed (use of broad-spectrum penicillins in the community (OR: 8.09 (1.9–35.6), p = 0.01); fluoroquinolones/cephalosporins in hospitals (OR: 2.2 (1.2–4.3), p = 0.01; OR: 2.0 (1.1–3.7), p = 0.02)). Half of community CDI cases were undetected because of absence of clinical suspicion, accounting for three times more undiagnosed adults in the community compared with hospitals (ca 111,000 vs 37,000 cases/year in Europe). Conclusion These findings support recommendations for improving diagnosis in patients presenting with diarrhoea in the community, to guide good practice to limit the spread of CDI.
LMNA Variants and Risk of Adult-Onset Cardiac Disease
Authors: Julieta Lazarte, Sean J. Jurgens, Seung Hoan Choi, Shaan Khurshid, Valerie N. Morrill, Lu-Chen Weng, Victor Nauffal, James P. Pirruccello, Jennifer L. Halford, Robert A. Hegele, Patrick T. Ellinor, Kathryn L. Lunetta, Steven A. Lubitz
Journal: Journal of the American College of Cardiology (2022)
P-30 First-line (1L) treatment patterns in advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma (GC/GEJC/EAC): Data from the Spanish AGAMENON-SEOM registry
Authors: P. Jiménez-Fonseca, A. Carmona-Bayonas, J. Gallego Plazas, A. Custodio, L. Visa, E. Martínez de Castro, L. Gómez González, M. Moreno Gutierrez, C. Polanco Sanchez, H. Xiao
Journal: Annals of Oncology (2022)
Systematic exploration of optimized base editing gRNA design and pleiotropic effects with BExplorer
Authors: Gongchen Zhang, Chenyu Zhu, Xiaohan Chen, Jifang Yan, Dongyu Xue, Zixuan Wei, Guohui Chuai, Qi Liu
Journal: Genomics Proteomics & Bioinformatics (2022)

Abstract Base editing technology is being increasingly applied in genome engineering, but the current strategy for designing guide RNAs (gRNAs) relies substantially on empirical experience rather than a dependable and efficient in silico design. Furthermore, the pleiotropic effect of base editing on disease treatment remains unexplored, which prevents its further clinical usage. Here, we presented BExplorer, an integrated and comprehensive computational pipeline to optimize the design of gRNAs for 26 existing types of base editors in silico. Using BExplorer, we described its results for two types of mainstream base editors, BE3 and ABE7.10, and evaluated the pleiotropic effects of the corresponding base editing loci. BExplorer revealed 524 and 900 editable pathogenic single nucleotide polymorphism (SNP) loci in the human genome together with the selected optimized gRNAs for BE3 and ABE7.10, respectively. In addition, the impact of 707 edited pathogenic SNP loci following base editing on 131 diseases was systematically explored by revealing their pleiotropic effects, indicating that base editing should be carefully utilized given the potential pleiotropic effects. Collectively, the systematic exploration of optimized base editing gRNA design and the corresponding pleiotropic effects with BExplorer provides a computational basis for applying base editing in disease treatment.
SO-17 A randomized, open-label, multicenter, phase III study of high-dose vitamin C plus FOLFOX +/- bevacizumab versus FOLFOX +/- bevacizumab as first-line treatment in patients with unresectable metastatic colorectal cancer
Authors: F. Wang, J. Xiao, Y. Zhang, X. Yuan, M. He, W. Fang, Y. Zhang, W. Wang, X. Hu, Z. Ma, Y. Yao, Z. Zhuang, F. Zhou, J. Ying, Y. Yuan, Q. Zou, Z. Guo, X. Wu, Y. Jin, Z. Mai, Y. Guo, R. Xu
Journal: Annals of Oncology (2022)
Successful resection of a 16-cm half-circumferential lesion at the greater curvature of the stomach using the endoscopic submucosal large-tunnel method
Authors: Hideyuki Chiba, Takayuki Kato, Tsuneyuki Takimoto, Kosuke Seita, Yu Ebisawa, Keiichi Ashikari
Journal: Endoscopy (2022)

Gastric endoscopic submucosal dissection (ESD) has become widespread since the development of endodevices and assistance methods. However, as the size of tumors being treated increases, one traction device alone is often not sufficient to apply countertraction. Lesions in the greater curvature are particularly challenging owing to their high risk of bleeding and perforation, and the tendency to accumulate fluid and blood. We report a case of ESD for a giant lesion using the submucosal large-tunnel method.
P-222 GA CPI 613: A single-arm, open-label phase I study of CPI-613 in combination with gemcitabine and nab-paclitaxel for patients with locally advanced or metastatic pancreatic cancer
Authors: A. Alistar, B. Morris, S. Luther, T. Pardee, N. Morganstein, J. Alpert, N. Burak
Journal: Annals of Oncology (2022)

Pancreatic cancer is the third leading cause of cancer death in the USA with current standard of care treatments that have moderate toxicity and median overall survival of less than 12 months. Safer and more effective treatments are needed. The glycolic and mitochondrial metabolism are aberrant in pancreatic cancer and translate into chemoresistance. Inhibition of glutamine metabolism can potentially synergize with therapies that increase intracellular reactive oxygen species such as Nab-Paclitaxel. CPI- 613 is a novel antimitocondrial developed by Rafael Pharmaceuticals. Preclinical data suggests possible synergy of CPI- 613 with nab-paclitaxel. This is a single-arm, open-label, nonblinded phase I study of CPI-613 in combination with gemcitabine and nab-paclitaxel in patients with locally advanced or metastatic pancreatic cancer. Key eligibility criteria include: histologically or cytologically documented and measurable locally advanced and metastatic pancreatic adenocarcinoma, ECOG performance status 0-2, first-line systemic treatment. CPI-613 infused intravenously with a starting dose of 500 mg/m2 followed by modified dose nab-paclitaxel and gemcitabine on day 1, 8, 15 of a 28-day cycle. The study is comprised of a two-stage dose-escalation schema to evaluate the MTD of CPI-613. At least six months of treatment was planned for patients who have a response. Primary endpoint of the study is MTD of CPI 613 when combined with gemcitabine and nab-paclitaxel and secondary endpoints of the study are treatment related adverse events and clinical response to treatment. This study was initiated in February 2018 at Atlantic Health System and has completed accrual in December 2019. Clinical trial information: NCT03435289. 26 patients were screened, and 23 patients were enrolled, with 22 patients evaluable. The MTD of CPI- 613 was determined at 1500mg/m2; all patients are off treatment. The median OS for patients treated at 500 mg/m2 was 20.8 mo and PFS was 6.4 mo, the median OS for patients treated at 1000 mg /m2 was 10.3 mo and PFS was 5.0 mo and the median OS for 1500 mg/m2 was 9.2 mo and PFS was 3.5 mo. The treatment was well tolerated overall with expected toxicity mainly related to chemotherapy (such as fatigue, neuropathy, hematologic toxicity). The results prove that the treatment is feasible, and CPI 613 shows clinical synergy with chemotherapy. Further expansion of the combination in a multisite setting is being evaluated.